title: MAVS-dependent IRF3/7 bypass of interferon β-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells.
abstract: Measles virus (MV) infects CD150Tg/Ifnar (IFN alpha receptor)(-/-) mice but not CD150 (a human MV receptor)-transgenic (Tg) mice. We have shown that bone marrow-derived dendritic cells (BMDCs) from CD150Tg/Ifnar(-/-) mice are permissive to MV in contrast to those from simple CD150Tg mice, which reveals a crucial role of type I interferon (IFN) in natural tropism against MV. Yet, the mechanism whereby BMDCs produce initial type I IFN has not been elucidated in MV infection. RNA virus infection usually allows cells to generate double-stranded RNA and induce activation of IFN regulatory factor (IRF) 3/7 transcription factors, leading to the production of type I IFN through the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5)-mitochondrial antiviral signaling protein (MAVS) pathway. In mouse experimental BMDCs models, we found CD150Tg/Mavs(-/-)BMDCs, but not CD150Tg/Irf3(-/-)/Irf7(-/-)BMDCs, permissive to MV. IFN-α/β were not induced in MV-infected CD150Tg/Mavs(-/-)BMDCs, while IFN-β was subtly induced in CD150Tg/Irf3(-/-)/Irf7(-/-)BMDCs. In vivo systemic infection was therefore established by transfer of MV-infected CD150Tg/Mavs(-/-) BMDCs to CD150Tg/Ifnar(-/-) mice. These data indicate that MAVS-dependent, IRF3/7-independent IFN-β induction triggers the activation of the IFNAR pathway so as to restrict the spread of MV by infected BMDCs. Hence, MAVS participates in the initial induction of type I IFN in BMDCs and IFNAR protects against MV spreading. We also showed the importance of IL-10-producing CD4(+) T cells induced by MV-infected BMDCs in vitro, which may account for immune modulation due to the functional aberration of DCs.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Takaki
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Fukiko
authors.initials: F
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ebihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshiumi
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Shingai
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008457:Measles / Q000276:immunology*; D008459:Measles virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014709:Vero Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C512612:MAVS protein, mouse; C494235:Irf7 protein, mouse; C000604059:SLAMF1 protein, human; C476286:Ticam1 protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse
keywords: BM; Dendritic cells; Innate immunity; MAVS; MDA5; MV; Measles virus; Mitochondrial antiviral signaling protein (MAVS); RIG-I; TICAM1; Toll/IL-1 receptor homology domain-containing adaptor molecule 1; Type I interferon; WT; bone marrow; measles virus; melanoma differentiation associated gene 5; mitochondrial antiviral signaling protein; retinoic acid inducible gene-I; wild-type